rs213950

chr7-117559479-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):c.1408G>A(p.Val470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,597,726 control chromosomes in the GnomAD database, including 164,304 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V470E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.56 (26569 hom., cov: 31)
  • Exomes 𝑓: 0.43 (137735 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 2.57

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000492.4
• BP4: Computational evidence support a benign effect (MetaRNN=9.284489E-7).
• BP6: Variant 7-117559479-G-A is Benign according to our data. Variant chr7-117559479-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 7130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117559479-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1408G>A	p.Val470Met	missense_variant	11/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.221+1254C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1408G>A	p.Val470Met	missense_variant	11/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84573 AN: 151846 Hom.: 26503 Cov.: 31

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.507

GnomAD3 exomes AF: 0.475 AC: 119239 AN: 251166 Hom.: 30261 AF XY: 0.464 AC XY: 63030 AN XY: 135772

Gnomad AFR exome AF: 0.871

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.420

Gnomad SAS exome AF: 0.480

Gnomad FIN exome AF: 0.549

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.427 AC: 616894 AN: 1445762 Hom.: 137735 Cov.: 30 AF XY: 0.427 AC XY: 307171 AN XY: 720158

Gnomad4 AFR exome AF: 0.881

Gnomad4 AMR exome AF: 0.521

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.406

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.547

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.438

GnomAD4 genome AF: 0.557 AC: 84699 AN: 151964 Hom.: 26569 Cov.: 31 AF XY: 0.561 AC XY: 41636 AN XY: 74256

Gnomad4 AFR AF: 0.861

Gnomad4 AMR AF: 0.518

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.419

Gnomad4 SAS AF: 0.488

Gnomad4 FIN AF: 0.562

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.510

Alfa AF: 0.423 Hom.: 33960

Bravo AF: 0.564

TwinsUK AF: 0.403 AC: 1493

ALSPAC AF: 0.391 AC: 1507

ESP6500AA AF: 0.850 AC: 3747

ESP6500EA AF: 0.468 AC: 4026

ExAC AF: 0.483 AC: 58619

Asia WGS AF: 0.527 AC: 1834 AN: 3478

EpiCase AF: 0.394

EpiControl AF: 0.390

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 15, 2008	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cystic fibrosis Benign:7

Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Apr 03, 2020	- -
Benign, no assertion criteria provided	literature only	OMIM	Nov 01, 1990	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	- -

CFTR-related disorder Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 19, 2021	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Apr 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	14
Dann	Benign	0.72
DEOGEN2	Uncertain	0.53	D;.;.;T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.68	T;T;T;T;T
MetaRNN	Benign	9.3e-7	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.14	N;.;.;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.48	N;.;.;N;.
REVEL	Uncertain	0.46
Sift	Benign	1.0	T;.;.;T;.
Sift4G	Benign	1.0	T;.;.;T;.
Polyphen		0.0	B;.;.;.;.
Vest4		0.069
MPC		0.0040
ClinPred		0.0091	T
GERP RS		3.0
Varity_R		0.23
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs213950; hg19: chr7-117199533; COSMIC: COSV50040905; COSMIC: COSV50040905;